Unraveling the enigma of salivary uric acid in periodontitis: Independent association, mechanistic insights, and future trajectories

Abstract

This article explores the association between salivary uric acid (UA) and periodontitis, systematically analyzing its dual roles and research progress. Studies indicate that UA acts as a primary antioxidant in saliva under physiological conditions (accounting for 70%), protecting periodontal tissues by scavenging reactive oxygen species. However, when gum disease becomes severe, UA can switch roles and fuel inflammation, worsening tissue damage. Lorente et al’s research found an independent inverse correlation between salivary UA levels and periodontitis severity (odds ratio = 6.14, P = 0.001), establishing 111 nmol/mL as a diagnostic threshold (area under the curve = 66%). Nevertheless, limitations include sample heterogeneity and failure to distinguish between gingivitis and periodontitis. Mechanistically, three hypotheses are proposed: The Antioxidant Depletion Hypothesis (UA oxidation consumption leading to feedback loops), the Microbial Metabolic Hijacking Hypothesis (pathogens utilizing UA as a carbon source to disrupt redox balance), and the Epithelial Barrier Dysfunction Hypothesis (UA deficiency causing downregulation of tight junction proteins). Future research should prioritize longitudinal cohorts to validate predictive value, integrate multi-omics to explore dysregulated signatures, and develop UA supplementation or targeted antioxidant therapies. This study provides novel insights into periodontitis diagnosis and mechanisms, advancing the application of salivary biomarkers in precision periodontics.

Key Words: Diagnostic biomarkers; Mechanistic hypotheses; Oxidative stress; Periodontitis; Salivary uric acid

Core Tip: This article delves into salivary uric acid's (UA) dual role in periodontitis—antioxidant under normal conditions and pro-inflammatory under pathology. Studies show an inverse link between UA levels and periodontitis severity, with 111 nmol/mL as a diagnostic marker. Future research should prioritize longitudinal validation, multi-omics analysis, and therapeutic strategies.

INTRODUCTION

The intricate interplay between oxidative stress and periodontal inflammation has long intrigued researchers, with emerging evidence highlighting the role of salivary biomarkers in elucidating disease pathogenesis. In this context, the study by Lorente et al[1] represents a pivotal contribution to the field, demonstrating an independent inverse association between salivary uric acid (UA) levels and periodontitis severity. This editorial contextualizes their findings within the broader landscape of UA-periodontitis research, critiques methodological nuances, and proposes actionable avenues for future exploration.

CURRENT LANDSCAPE: THE DUAL ROLE OF UA

Under physiological conditions, UA serves as the primary antioxidant in saliva, contributing to approximately 70% of its total antioxidative capacity[2]. A meta-analysis corroborated this dichotomy, revealing a 23% reduction in salivary UA among periodontitis patients compared to healthy controls[2]. Its function exhibits a dual nature: On one hand, the level of UA in saliva is positively correlated with the levels of anti-inflammatory markers after periodontal treatment, suggesting its involvement in the regulation of local inflammation[3,4]; on the other hand, there is a relationship between the UA levels in saliva and serum. Multiple cross-sectional studies have demonstrated that when serum UA levels rise (hyperuricemia), the concentration of salivary UA in gingival crevicular fluid also increases simultaneously[2,4]. This change in the permeability of the blood-saliva barrier may serve as a molecular bridge linking systemic inflammation.

Under pathological conditions, hyperuricemia transforms UA into a pro-inflammatory mediator by activating the NLRP3 inflammasome, promoting the polarization of M1-type macrophages and stimulating the release of pro-inflammatory cytokines, thereby exacerbating local periodontal oxidative stress and bone resorption[5]. This mechanism shares a high degree of overlap with the inflammatory pathways in gouty arthritis. Clinical data indicate that the incidence of severe periodontitis (stages III/IV) is significantly higher in patients with hyperuricemia[6,7], suggesting that the two conditions may share a common pathological axis of "oxidative stress-systemic inflammation-tissue destruction." It is particularly noteworthy that the systemic low-grade inflammation induced by hyperuricemia (such as elevated levels of tumour necrosis factor-alpha and interleukin-6) can further exacerbate metabolic disorders (obesity, diabetes). In turn, these metabolic diseases contribute to systemic inflammation through mechanisms like gut microbiota dysbiosis and lipopolysaccharide (LPS) translocation, forming a vicious cycle that increases the risk of periodontitis.

The clinical value of salivary UA also lies in its potential as a biomarker for the "oral-systemic axis." Studies have found a negative correlation between the activity of salivary antioxidant enzymes (such as superoxide dismutase) and UA levels in patients with periodontitis[8]. Moreover, LPS release resulting from oral microbiota dysbiosis can activate liver inflammation through the Toll-like receptor 4 signaling pathway[9]. This interplay between local and systemic inflammation positions salivary UA as a crucial link connecting metabolic diseases, hyperuricemia, and periodontitis. Notably, reduced salivary UA levels in patients with periodontitis may indicate the depletion of local antioxidant defenses, reflecting the dynamic interaction between microbial attacks and host protective mechanisms.

STRENGTHS AND LIMITATIONS OF THE LORENTE ET AL’S STUDY

The study by Lorente et al[1] represents a significant advancement in this field. One of its notable strengths lies in its prospective and observational design, which allows for a more accurate assessment of the relationship between salivary UA levels and periodontitis. By measuring salivary UA levels in subjects with and without periodontitis, the researchers were able to establish a clear association between low salivary UA levels and the disease, even after controlling for confounding factors such as age, smoking history, and arterial hypertension.

Furthermore, the study employed a comprehensive statistical analysis, including multivariate regression analysis and receiver operating characteristic curve analysis. These methods not only confirmed the independent association between salivary UA levels and periodontitis but also provided valuable insights into the diagnostic performance of salivary UA levels in predicting the disease. The identification of a cutoff point of 111 nmol/mL for salivary UA levels, below which the risk of periodontitis was significantly increased, holds promise for potential clinical applications.

Despite its significant contributions, this study is not without limitations. The relatively small sample size may have limited the statistical power of the analysis, potentially leading to an underestimation of the true association between salivary UA levels and periodontitis. Moreover, the inclusion of subjects with localized gingivitis in the non-periodontitis group may have confounded the results, as gingivitis and periodontitis represent different stages of the same disease continuum. Future studies with larger sample sizes and more homogeneous subject groups are needed to address these limitations and validate the findings. To overcome these limitations and validate the results, future research should involve larger sample sizes and more homogeneous subject groups. Although the diagnostic cutoff value of 111 nmol/mL shows promise, its clinical applicability needs to be validated against established periodontal indices, such as the community periodontal index and clinical attachment loss, and compared with systemic UA thresholds. Additionally, future studies ought to explore population-specific variations, including factors like age and ethnicity, to enhance its generalizability.

It is worth noting that the study by Lorente et al[1] is not sufficient to elucidate the causal relationship between dysfunctional salivary UA and periodontitis. In other words, it cannot determine whether dysfunctional salivary UA is a consequence of periodontitis rather than a causative factor. In contrast, the longitudinal study conducted by Wu et al[5] revealed that UA depletion occurs prior to the progression of periodontitis. This finding offers a fresh perspective for investigating the causal link between UA and periodontitis and further underscores the necessity of in-depth research into the role of UA in the pathogenesis of periodontitis. This research theme, which explores the impact and mechanisms of hyperuricemia on periodontitis, is thus both relevant and enlightening.

Finally, although Lorente et al’s study[1] accounted for confounding variables such as age, smoking, and hypertension, it did not exclude patients with systemic conditions that are recognized to influence serum UA levels, such as metabolic syndrome and chronic kidney disease. Consequently, future studies ought to implement stricter inclusion criteria to differentiate the local effects of salivary UA from systemic metabolic disruptions.

MECHANISTIC HYPOTHESES UNDERPINNING UA DYNAMICS

The intricate dual role of UA in periodontitis can be elucidated through three interconnected mechanistic pathways (Table 1).

Table 1 Tripartite mechanisms linking salivary uric acid dysfunction to periodontitis.

Mechanism	Brief description	Key interactions
Antioxidant depletion	Chronic inflammation oxidizes UA, depleting reserves and impairing antioxidant capacity	ROS from inflammation oxidize UA. UA depletion reduces antioxidant defense. Oxidative stress fuels inflammation
Microbial metabolic hijacking	Pathogens use UA as a carbon source, disrupting redox balance and promoting inflammation	UA depletion correlates with elevated microbial metabolites. Short-chain fatty acids activate NF-κB, exacerbating inflammation
Epithelial barrier dysfunction	UA deficiency weakens epithelial integrity, facilitating microbial translocation and tissue damage	UA deficiency reduces tight junction proteins. Increased microbial translocation triggers immune responses and tissue destruction
Synergistic cycle	Pathways interact, forming a vicious cycle of inflammation, oxidation, and infection	Microbial metabolism consumes UA and produces ROS. Barrier disruption enhances pathogen invasion

UA: Uric acid; ROS: Reactive oxygen species; NF-κB: Nuclear factor-kappaB.

Antioxidant depletion hypothesis

A self-perpetuating cycle of oxidative stress emerges as chronic periodontitis-associated inflammation triggers the generation of reactive oxygen species (ROS), which directly oxidize salivary UA[10]. This UA oxidation depletes its antioxidant reserves in saliva, compromising the oral cavity’s radical-scavenging capacity. The resultant oxidative imbalance further fuels inflammation, creating a bidirectional feedback loop that amplifies tissue damage[10]. Meta-analyses corroborate this mechanism, revealing significantly lower salivary/gingival crevicular fluid UA levels in periodontitis patients compared to healthy controls, with UA concentrations inversely correlating with oxidative stress biomarkers like malondialdehyde[4]. Notably, animal models demonstrate that UA supplementation reverses these effects. For example, Wu et al[5] showed that UA administration reduced alveolar bone loss and suppressed pro-inflammatory cytokines in ligature-induced periodontitis mice, highlighting its therapeutic potential. These findings suggest that UA’s antioxidant function is not merely passive but dynamically linked to periodontal health, with its depletion representing both a biomarker of disease severity and a driver of pathogenesis.

Microbial metabolic hijacking hypothesis

Pathogens undergo metabolic reprogramming where periodontopathic bacteria (e.g., Porphyromonas gingivalis) may repurpose UA as a carbon source, utilizing xanthine oxidase pathways (these pathways catalyze the oxidation of purine substrates to UA, generating ROS in the process, and are linked to purine metabolism disorders and diseases like gout, cancer, and diabetes) to fuel their proliferation[11]. This metabolic hijacking disrupts host-microbiome redox homeostasis, collapsing localized antioxidant defenses. Metabolomic studies corroborate this mechanism, showing low UA levels associated with elevated oral microbial metabolites (e.g., propionate, butyrate)[12]. These short-chain fatty acids exacerbate inflammation through nuclear factor-kappaB activation, creating a dysbiotic microenvironment. Low UA status is significantly associated with notable alterations in amino acid metabolism, particularly tryptophan metabolism, as well as lipid metabolism pathways. In patients with recurrent aphthous ulcers, reduced UA levels are accompanied by the enrichment of specific microorganisms, such as Rothia and Prevotella. These microbial communities generate distinct metabolites by modulating purine and caffeine metabolic pathways[13]. In patients with chronic spontaneous urticaria, there is a significant correlation between decreased UA levels and abnormal unsaturated fatty acid metabolism linked to gut/oral microbiota dysbiosis[14]. Collectively, these findings suggest a bidirectional regulatory relationship between reduced UA levels and changes in oral microbial metabolites. This relationship not only positions UA as a potential disease biomarker but also offers new insights into interventions for metabolic oral diseases. For instance, modulating the gut-oral microbiota axis and targeting specific microbial metabolites, such as butyrate or tryptophan metabolites, may improve UA metabolic disorders. However, further research is required to elucidate the precise mechanisms by which microbial metabolites directly regulate UA levels.

Epithelial barrier dysfunction hypothesis

Tight junction proteins are membrane-associated components forming a barrier at cell junctions, sealing intercellular gaps to control paracellular passage and sustain epithelial/endothelial integrity and adhesion. UA deficiency impairs gingival epithelial integrity by downregulating tight junction proteins (e.g., occluding). facilitating microbial translocation into deeper tissues[12]. This breach triggers exaggerated immune responses, perpetuating tissue destruction[15].

UA levels in serum, saliva, and gingival crevicular fluid are associated with periodontal diseases, yet the specific underlying mechanisms remain controversial. Physiological UA concentrations neutralize peroxynitrite to exert antioxidative effects, whereas pathological hyperuricemia promotes pro-inflammatory transitions. Notably, serum hyperuricemia may exacerbate periodontitis via systemic inflammation, while low salivary UA reflects compromised local redox capacity. Some studies suggest that elevated UA levels may exacerbate periodontal tissue destruction through pro-inflammatory and pro-oxidative effects[12]. In contrast, other research indicates that estrogen (E2) can protect the gingival epithelial barrier from LPS-induced damage by upregulating the expression of tight-junction proteins[16]. Experimental evidence demonstrates that virulence factors of Porphyromonas gingivalis, such as gingipains, can disrupt the intestinal epithelial barrier by degrading the tight-junction protein occludin[17]. This finding implies that oral pathogens might damage the gingival epithelial barrier through similar mechanisms.

Once the epithelial barrier is compromised, microbial products like LPS can translocate into the bloodstream, triggering an inflammatory response and subsequently leading to periodontal tissue inflammation. This disruption sets off a vicious cycle of "microbial translocation-immune activation-tissue destruction". Future studies are warranted to further elucidate the biphasic mechanisms of UA in the oral/gingival epithelial barrier.

FUTURE DIRECTIONS

To advance our understanding of the relationship between salivary UA levels and periodontitis, several key research directions and considerations are necessary.

First and foremost, large-scale longitudinal cohort studies are required. These studies should place a high priority on standardized patient stratification. Specifically, it is crucial to exclude individuals with confounding comorbidities, such as gout and renal impairment. By doing so, we can clarify the specificity of salivary UA as a biomarker for periodontitis. Moreover, conducting multi-center studies with harmonized eligibility criteria is of great importance. This approach will further improve the robustness of UA-based diagnostics. As a result, we will be able to conduct a more in-depth investigation into the independent association between salivary UA levels and periodontitis, as well as the long-term impact of salivary UA levels on disease progression.

Second, studies should aim to elucidate the precise mechanisms by which salivary UA levels influence periodontitis. This involves exploring the role of oxidative stress, inflammation, and microbial metabolism in this process. Understanding these mechanisms will provide a solid foundation for developing targeted interventions.

Third, translational research is essential to develop novel diagnostic and therapeutic strategies based on the findings of these studies. For instance, measuring salivary UA levels could potentially be incorporated into routine clinical practice as a non-invasive biomarker for periodontitis risk assessment. This would offer a convenient and cost-effective way to identify individuals at high risk of developing periodontitis. Additionally, the development of antioxidant-based therapies, such as UA-containing mouthwashes or gels, may open up new avenues for the prevention and treatment of periodontitis.

However, when it comes to clinical implementation, we must take into account various confounders. These include salivary flow rate, dietary purine intake, and oral hygiene practices. Standardized sampling protocols, such as fasting collections and plaque control, are essential for obtaining reliable measurements of salivary UA levels.

Furthermore, it is worth reiterating that in longitudinal cohorts, standardized patient stratification is of utmost importance. This includes the exclusion of individuals with confounding comorbidities, like gout and renal impairment, to clarify the specificity of salivary UA as a periodontitis biomarker. Multi-center studies with harmonized eligibility criteria will undoubtedly further enhance the robustness of UA-based diagnostics, paving the way for more accurate diagnosis and effective treatment of periodontitis.

CONCLUSION

In summary, salivary UA’s dual role as both protector and pathogen in periodontitis underscores its potential as a precision biomarker and therapeutic target. Further validation of these mechanisms will pave the way for non-invasive diagnostics and UA-modulating therapies in periodontal care. Taken together, these findings highlight the remarkable utility of salivary UA in advancing precision periodontics.